Chapter 17 Alcohols and Phenols Alcohols and Phenols ...
Chapter 17
Alcohols and Phenols
Alcohols and Phenols - alcohols OH
- compounds that have hydroxyl groups bonded to saturated, sp3-hybridized carbon atoms
- phenols OH
- compounds that have hydroxyl groups bonded to aromatic rings
- enols OH
- compounds that have a hydroxyl group bonded to a vinylic carbon
C
C
Naming Alcohols and Phenols - classified as primary (1o), secondary (2o), or tertiary (3o) H R
C
H OH
R
C
R OH
R
C
OH
H
R
R
primary (1o)
secondary (2o)
tertiary (2o)
- named as derivatives of the parent alkane
1
Rules for Alcohols 1) Select longest carbon chain containing the hydroxyl group; derive the parent name -e with -ol 2) Number the alkane chain beginning at the end nearer the hydroxyl group 3) Number substituents according to position on the chain and list substituents in alphabetical order
Examples: HO H CH 3
OH H3C
C
CH CHCH 3
CH2CH2CH3
OH
CH3
HO H
2-methyl-2-pentanol
3-phenyl-2-butanol
cis-1,4-cyclohexanediol
Common Alcohols CH2OH
CH3 H2C
H3C
CHCH2OH
C
OH
CH3
allyl alcohol benzyl alcohol
tert-butyl alcohol
HOCH2 CH2OH
HOCH2 CHCH2OH OH
ethylene glycol
glycerol
Naming Phenols - “phenol” is both the name of the hydroxy compound and family name for hydroxy-substituted aromatic compounds
H3 C
OH
OH O2N
m-methylphenol
NO2
2,4-dinitrophenol
2
Properties of Alcohols and Phenols - alcohols and phenols have geometry nearly the same as water - R-O-H angle ~ 109o - oxygen atom is sp3 hybridized
Physical Properties of Alcohols - alcohols have much higher boiling points than hydrocarbons and alkyl halides Compound
Molecular Mass
1-propanol
60 g/mol
97 oC
butane
58 g/mol
-0.5 oC
chloroethane
65 g/mol
12.5 oC
Boiling Point
Comparison of Boiling Points
3
Physical Properties of Phenols - phenols have elevated boiling points relative to hydrocarbons
CH3
OH
phenol: bp = 181.7oC
toluene: bp = 110.6oC
Hydrogen Bonding by Alcohols and Phenols
Basicity and Acidity - alcohols and phenols are both weakly basic and weakly acidic - reversibly protonated by strong acids to yield oxonium ions, ROH2+ H H
O
+ H
X
H
H
O
X H
- dissociate slightly in dilute aqueous solution by donating a proton to water, generating H3O+ and alkoxide ion RO-, or a phenoxide ion, ArO-: H R
H + O
H
O
R H
O
+ H
O
H
4
Factors Affecting Basicity and Acidity Alcohols 1) solvation and steric effects - smaller substituents promote solvation of the alkoxide ion that results from dissociation CH3 H3C
H3C
O
C
O
CH3 methoxide ion, CH3O(pKa = 15.5)
t-butoxide ion, (CH3)3CO(pKa = 18.0)
- the more easily the alkoxide ion is solvated, the more stable it is - the more stable the alkoxide ion, the more acidic the parent alcohol
2) inductive effects - electron-withdrawing substitutents stabilize an alkoxide ion by spreading the charge over a large volume, making the alcohol more acidic CF3 F 3C
C
CH3 O
H3C
C
CF3
O
CH3
(pKa = 5.4)
(pKa = 18.0)
Generation of Alkoxides - alcohols react with alkali metals and with strong bases to form alkoxides CH3
CH3 H3C
C
OH +
2K
H3C
C
O K+ + H2
CH3
CH3
tert-butyl alcohol
potassium tert-butoxide
5
Examples CH3O- Na+ + H2
CH3OH + NaH
sodium methoxide
methanol
CH3CH2OH + NaNH2 ethanol
CH3CH2O- Na+ + H2 sodium ethoxide
O +MgBr + H2O
OH + CH3MgBr
bromomagnesium cyclohexoxide
cyclohexanol
Phenols - phenols are a million times more acidic than alcohols - greater acidity is because the phenoxide ion is resonance-stabilized - delocalization of the negative charge over the ortho and para positions of the aromatic ring results in increased stability of the phenoxide anion
O
O
EWG
EDG
- phenols with an electron-withdrawing substituent are generally more acidic since the substitutents delocalize the negative charge - phenols with an electron-donating substituent are generally less acidic since the substitutents destabilize the phenoxide ion
Resonance Stabilization of the Phenoxide Ion
6
Preparation of Alcohols Review 1) hydration of alkenes by way of hydroboration/oxidation and oxymercuration/reduction H3C
H3C
H
BH3 THF
-OH
BH2
H
OH
H
CH3
1-methylcyclohexene
H
H2O2
trans-2-methylcyclohexanol H3C Hg(OAc)2
NaBH4
OH
H2 O
H3C OH
H HgOAc
1-methylcyclohexanol
2) hydroxylation of an alkene with OsO4 followed by reduction with NaHSO3 H3C OsO4
O
O Os
pyridine
H
O
O
H
Hg(OAc)2 H2 O
OH
OH
1-methylcis-1,2-cyclohexanediol
CH3
1-methylcyclohexene
H3C NaHSO3
CH3 O H
1-methyl-1,2-epoxycyclohexane
HO H3O+
H
CH3 OH
1-methyltrans-1,2-cyclohexanediol
7
Reduction of Carbonyl Compounds O
OH
[H]
C
C
Reduction of Aldehydes and Ketones - aldehydes are reduced to primary alcohols and ketones are reduced to secondary alcohols OH
O [H]
C
R
R
H
aldehyde
C H
primary alcohol
OH
O R
H
[H]
C
R
R'
ketone
C R'
H
secondary alcohol
Reagents for Aldehyde and Ketone Reduction O CH3CH2CH2
C
OH
1. NaBH4, EtOH
H
H3CH2CH2C
2. H3O+
C
H
H
butanal
1-butanol (85%) O
OH
H
1. NaBH4, EtOH
C
C
2. H3O+
dicyclohexyl ketone
dicyclohexylmethanol (88%)
O
OH
H 1. LiAlH4, ether 2. H3
2-cyclohexanone
C
O+
- sodium borohydride NaBH4 is usually chosen because of its safety and ease of handling
2-cyclohexenol
8
Reduction of Carboxylic Acids and Esters
O R
C
O
or OH
R
C
OH
[H] R
OR'
C H
H
primary alcohol
- carboxylic acids and esters are reduced to give primary alcohols
Examples O CH 3(CH 2)7CH
CH(CH 2)7 COH
1. LiAlH4, ether 2. H3O+
9-octadecenoic acid
CH(CH2)7CH2OH
9-octadecen-1-ol (87%)
O CH3CH2CH
CH3(CH2)7CH
CH COCH3
1. LiAlH4, ether
CH3CH2CH
CHCH2OH
2. H3O+
methyl-2-pentenoate
2-penten-1-ol (91%)
- NaBH4 reduces esters slowly and does not reduce carboxylic acids; LiAlH4 reduces all carbonyl groups
Mechanism - can be regarded to involve attack of a hydride ion to the positively polarized, electrophilic carbon atom of the carbonyl group
O C
carbonyl compound
H
O C
OH
H
alkoxide intermediate
C
H
alcohol
- protonation by acid gives the alcohol
9
Reactions with Grignard Reagents R
X
R
MgX
Grignard reagent
R = 1o, 2o, or 3o alkyl, aryl, vinylic X = Cl, Br, or I
O
OH
1. RMgX, ether
C
C
2. H3O+
+ HOMgX R
Formaldehyde Reaction O
MgBr
+ H
cyclohexylmagnesium bromide
C
CH2OH
1. Mix 2. H3O+
H
formaldehyde
cyclohexylmethanol (65%)
Aldehyde Reaction CH3 H3C
C
O
MgBr
+
CH2 CH
1. ether solvent 2. H3
H
3-methylbutanal
CH3 H3C
O+
phenylmagnesium bromide
OH
C
CH2 C
H
H
3-methyl-1-phenyl-1butanol (73%)
Ketone Reaction O
OH
1. CH3CH2MgBr, ether 2. H3
CH2CH3
O+
cyclohexanone
1-ethylcyclohexanol (89%)
Ester Reaction O CH3CH2CH2CH2
C OCH2CH3
ethylpentanoate
1. CH3CH2MgBr, ether 2. H3
O+
OH CH3CH2CH2CH2
C CH3 CH3
2-methyl-2-hexanol (85%)
+ CH3CH2OH
10
Carboxylic Acid Reaction O
RMgBr
+ R'
C
O
RH + OH
R'
carboxylic acid
C
O
+MgBr
carboxylic acid salt
- carboxylic acids do not give addition products with Grignard reagents because the acidic carboxyl hydrogen reacts with the basic Grignard reagent to yield a hydrogen carbon (RH) and magnesium salt of the acid
Limitations of Grignard Reagents - Grignard reagent cannot be prepared from an organohalide if there are other reactive functional groups in the same molecule - this limits the structures of the products Br
FG
molecule
- Grignard cannot be made where FG = protonate Grignard
= -OH, -NH, -SH, -COOH
=
O
O
O
CH ,
CR ,
CNR2
C
N,
NO2 ,
adds to Grignard
SO2R
Mechanism
O C
carbonyl compound
R
O C
H3O+
R
alkoxide intermediate
OH C
R
alcohol
- Grignard reagent acts as a nucleophilic carbon anion, or carbanion; the addition of the Grignard is analogous to the addition of a hydride
11
Reactions of Alcohols H O
C-O reactions
O-H reactions
C
Dehydration of Alcohols (C-O bond) H
OH C
C
C
+
C
H2O
- a number of methods have been developed: 1) acid-catalyzed dehydration (mild) 2) acid-catalyzed dehydration (harsh) 3) phosphorus oxychloride
Acid-catalyzed dehydration H3C
CH3
OH H3O+, THF 50oC
1-methylcyclohexene (91%)
1-methylcyclohexanol
CH3 H3C
C
CH2CH3
OH 2-methyl-2butanol
H3O+, THF 25oC
CH3
CH3 CHCH3 +
CH3 2-methyl-2-butene (trisubstituted)
CH2CH3 CH3 2-methyl-1-butene (disubstituted)
- acid-catalyzed reaction follows Zaitsev’s rule, giving the more highly substituted alkene as major product - E1 mechanism that involves three steps
12
Reactivity OH
OH R
C
R
> R
C
OH H
>
C
R
R
R
H
H
reactivity - tertiary substrates always react fastest in E1 reactions because they lead to highly stabilize tertiary carbocation intermediates
Mechanism
Phosphorus Oxychloride
CH3 OH
CH3
POCl3 pyridine, OoC
H 1-methylcyclohexanol
1-methylcyclohexene (96%)
- E2 mechanism, -OPOCl2 is excellent leaving group - pyridine serves as both solvent and base
13
Mechanism
Conversion of Alcohols into Alkyl Halides (C-O Bond)
RCH2OH
RCH2OH
SOCl2
PBr3
RCH2Cl + SO2 + HCl
RCH2Br + HOPBr2
- tertiary alcohols are converted using HCl or HBr at OoC through an SN1 mechanism - secondary and primary alcohols are resistant to acid and are converted using either SOCl2 or PBr3 through an SN2 mechanism
Mechanism
14
Conversion of Alcohols into Tosylates (O-H Bond) CH3
R
O
H
alcohol
+
Cl O
CH3
pyridine S O
p-toluenesulfonyl chloride
R
O O
+
S O
tosylate
pyridine·HCl
- reaction produces alkyl tosylates which are synthetically useful since they behave like alkyl halides - in contrast to alkyl halides, the products undergo only one Walden inversion to form a product - the product is therefore of opposite stereochemistry relative to the reactants
15
Oxidation of Alcohols OH C
O
oxidize
H
C
reduce
Primary Alcohol OH R
C H
O
[O]
R
H
C
O
[O]
R
H
aldehyde
C
O
H
carboxylic acid
Secondary Alcohol OH R
C R'
O
[O]
R
H
C
R'
ketone
Tertiary Alcohol OH R
C R'
[O]
R''
NO REACTION
Reagents - large number of reagents can be used: KMnO4, CrO3, Na2CrO7 - depends on factors such as cost, convenience, reaction yield, and alcohol sensitivity
16
Preparation of an Aldehyde from a Primary Alcohol on Laboratory Scale - use of pyridinium chlorochromate (PCC) O
PCC CH2OH
C
CH2Cl2
citronellol
H
citronellal (82%) PCC =
N
H CrO3Cl-
- most other oxidizing agents oxidize primary alcohols to carboxylic acids O
CH3(CH2)8CH2OH
CrO3
CH3(CH2)8
H3O+, acetone
C
OH
decanoic acid (93%)
1-decanol
Secondary Alcohols to Give Ketones - large scale and inexpensive, use Na2Cr2O7: CH3 H3C
CH3
Na2Cr 2O7
C
OH
H3C
H2O, CH3CO2H, heat
CH3
C
O
CH3
4-tert-butylcyclohexanol
4-tert-butylcyclohexanone (91%)
- for sensitive alcohols, use PCC: CH3 O
CH3 OH
PCC
CH3
CH3
CH2Cl2, 25oC O
O
4-androstene-3,17-dione (82%)
testosterone
Mechanism - pathway closely related to E2 reaction
Base
O H
O O C
H
Cr
O
H
O Cr
O C
O O O
H
Cr O C
H
O
O
O
E2
H Base
chromate intermediate
C
carbonyl compound
- reaction produces a C-O bond (compare to C-C bond)
17
Protection of Alcohols - it is often necessary to circumvent synthetic incompatibilities using protecting groups 1) introduce the protecting group 2) carry out the desired reaction 3) remove the protecting group
Mg
HO CH2CH2CH2
x
Br
HO CH2CH2CH2
MgBr
Ether
Trimethylsilyl (TMS) ether - common protecting group for alcohols is trimethylsilyl (TMS) ether
CH3 ROH
alcohol
+
H3C
Si
Cl
(CH3CH2)3N
CH3 R
Si
CH3 +
(CH3CH2)3NH+ Cl-
CH3
CH3
chlorotrimethylsilane
O
a trimethylsilyl ether
Example OH
+ (CH3)3SiCl
cyclohexanol
(CH3CH2)3N
OSi(CH3)3
cyclohexyl trimethylsilyl ether (94%)
18
Removal of the Protecting Group - protecting group can be removed using acid or with fluoride ion
O
CH3
Si
OH
H3O+
+ (CH3)3SiOH
CH3
CH3
cyclohexanol
cyclohexyl TMS ether
Preparation of Phenols Dow Process Cl
OH 1. NaOH, H2O, 340oC, 2500 psi 2. H3O+
Alternative Synthesis H H3C
C
OOH CH3
O2
H3C
C
CH3
OH O
H3O+
+
heat
cumene
cumene hydroperoxide
phenol
H3C C CH 3
acetone
Mechanism
19
Acetal O
OR'
Acid
+ 2R’OH
C
C
catalyst
OR'
Hemiacetal OH C
OR'
Laboratory Preparation
OH
SO3H
SO3
1. NaOH, 300oC
H2SO4
2. H3O+
CH3
CH3
toluene
CH3
p-methylphenol (72%)
p-toluenesulfonic acid
- owing to the harsh reaction conditions, the reaction is limited to alkyl-substituted phenols
Uses of Phenols OH Cl
OCH2COOH Cl
Cl
Cl
Cl Cl
Cl
pentachlorophenol (wood preservative)
2,4-dichlorophenoxyacetic acid (herbicide) 3
OH Cl
Cl
OH
OH Cl
C(CH3)3
(H3C)3C
Cl Cl Cl
Cl
hexachlorophene (antiseptic)
CH3
butylated hydroxytoluene (food preservative)
20
Reactions of Phenols 1) Electrophilic Aromatic Substitution - -OH group is strongly activating, ortho- and para-directing - phenol is therefore highly reactive for electrophilic halogenation, nitration, sulfonation, Friedel-Crafts reactions Y HO
HO
Y
para-
ortho-
2) Oxidation of Phenols - oxidation yields 2,5-cyclohexadiene-1,4-dione or quinone - reactions can be accomplished with Na2Cr2O7 and (KSO3)2NO O
OH (KSO3)2NO H2O
O
phenol
benzoquinone (70%)
Reversible Oxidation - oxidation-reduction (redox) properties of quinones makes quinones a valuable class of compounds O
OH SnCl2, H2O Fremy’s salt
O
benzoquinone
OH
hydroquinone
21
Ubiquinones O H3CO
CH3 CH3 (CH2 CH CCH2)nH
H3CO O
- redox behavior is found in biology, where compounds known as ubiquinones act as biochemical oxidizing agents to mediate electron-transfer processes in the mitochondria
Energy Production in the Mitochondria O H3CO
OH CH3
H3CO
CH3
R
H3CO
R
+ NAD+
NADH + H+ + H3CO O
OH O
OH H3CO
CH3
H3CO
R
H3CO
CH3
H3CO
R
+ H2O
+ ½O2 O
OH
NADH + ½O2 + H+
NAD+ + H2O
Spectroscopy of Alcohols and Phenols Infrared Spectroscopy - alcohols characteristic O-H stretching absorption at 3300 - 3600 cm-1 - depends upon the extent of hydrogen bonding - unassociated: sharp absorption at 3600 cm-1 - hydrogen bonds: broad absorption at 3300 - 3400 cm-1 - strong C-O stretching band near 1050 cm-1 - phenols broad absorption at 3500 cm-1 plus aromatic bands at 1500 and 1600 cm-1
22
Infrared Spectrum of Cyclohexanol
Infrared Spectrum of Phenol
NMR Spectroscopy 69.5 δ
OH
- 13C NMR spectra:
35.5 δ 24.4 δ 25.9 δ
- 1H NMR spectra:
- hydrogens on oxygen-bearing carbons are deshielded (3.5. - 4.5 δ) - hydrogen atom of -OH undergoes exchange:
C
O
H
H’A
C
H
O
H'
O
D
H D2O
C
O
H
C
(can exchange hydrogen for deuterium)
23
1H
NMR Spectrum of 1-Propanol
Mass Spectrometry - alcohols fragment by two pathways: alpha cleavage and dehydration +.
+
OH R
C
OH CH2R
R
R
C
+ . CH2R
R
+.
+. OH
H C
C
H2O +
C
C
- both fragments are apparent in mass spectra
Mass Spectrum of 1-Butanol
24
Alcohols and Phenols
Alcohols and Phenols - alcohols OH
- compounds that have hydroxyl groups bonded to saturated, sp3-hybridized carbon atoms
- phenols OH
- compounds that have hydroxyl groups bonded to aromatic rings
- enols OH
- compounds that have a hydroxyl group bonded to a vinylic carbon
C
C
Naming Alcohols and Phenols - classified as primary (1o), secondary (2o), or tertiary (3o) H R
C
H OH
R
C
R OH
R
C
OH
H
R
R
primary (1o)
secondary (2o)
tertiary (2o)
- named as derivatives of the parent alkane
1
Rules for Alcohols 1) Select longest carbon chain containing the hydroxyl group; derive the parent name -e with -ol 2) Number the alkane chain beginning at the end nearer the hydroxyl group 3) Number substituents according to position on the chain and list substituents in alphabetical order
Examples: HO H CH 3
OH H3C
C
CH CHCH 3
CH2CH2CH3
OH
CH3
HO H
2-methyl-2-pentanol
3-phenyl-2-butanol
cis-1,4-cyclohexanediol
Common Alcohols CH2OH
CH3 H2C
H3C
CHCH2OH
C
OH
CH3
allyl alcohol benzyl alcohol
tert-butyl alcohol
HOCH2 CH2OH
HOCH2 CHCH2OH OH
ethylene glycol
glycerol
Naming Phenols - “phenol” is both the name of the hydroxy compound and family name for hydroxy-substituted aromatic compounds
H3 C
OH
OH O2N
m-methylphenol
NO2
2,4-dinitrophenol
2
Properties of Alcohols and Phenols - alcohols and phenols have geometry nearly the same as water - R-O-H angle ~ 109o - oxygen atom is sp3 hybridized
Physical Properties of Alcohols - alcohols have much higher boiling points than hydrocarbons and alkyl halides Compound
Molecular Mass
1-propanol
60 g/mol
97 oC
butane
58 g/mol
-0.5 oC
chloroethane
65 g/mol
12.5 oC
Boiling Point
Comparison of Boiling Points
3
Physical Properties of Phenols - phenols have elevated boiling points relative to hydrocarbons
CH3
OH
phenol: bp = 181.7oC
toluene: bp = 110.6oC
Hydrogen Bonding by Alcohols and Phenols
Basicity and Acidity - alcohols and phenols are both weakly basic and weakly acidic - reversibly protonated by strong acids to yield oxonium ions, ROH2+ H H
O
+ H
X
H
H
O
X H
- dissociate slightly in dilute aqueous solution by donating a proton to water, generating H3O+ and alkoxide ion RO-, or a phenoxide ion, ArO-: H R
H + O
H
O
R H
O
+ H
O
H
4
Factors Affecting Basicity and Acidity Alcohols 1) solvation and steric effects - smaller substituents promote solvation of the alkoxide ion that results from dissociation CH3 H3C
H3C
O
C
O
CH3 methoxide ion, CH3O(pKa = 15.5)
t-butoxide ion, (CH3)3CO(pKa = 18.0)
- the more easily the alkoxide ion is solvated, the more stable it is - the more stable the alkoxide ion, the more acidic the parent alcohol
2) inductive effects - electron-withdrawing substitutents stabilize an alkoxide ion by spreading the charge over a large volume, making the alcohol more acidic CF3 F 3C
C
CH3 O
H3C
C
CF3
O
CH3
(pKa = 5.4)
(pKa = 18.0)
Generation of Alkoxides - alcohols react with alkali metals and with strong bases to form alkoxides CH3
CH3 H3C
C
OH +
2K
H3C
C
O K+ + H2
CH3
CH3
tert-butyl alcohol
potassium tert-butoxide
5
Examples CH3O- Na+ + H2
CH3OH + NaH
sodium methoxide
methanol
CH3CH2OH + NaNH2 ethanol
CH3CH2O- Na+ + H2 sodium ethoxide
O +MgBr + H2O
OH + CH3MgBr
bromomagnesium cyclohexoxide
cyclohexanol
Phenols - phenols are a million times more acidic than alcohols - greater acidity is because the phenoxide ion is resonance-stabilized - delocalization of the negative charge over the ortho and para positions of the aromatic ring results in increased stability of the phenoxide anion
O
O
EWG
EDG
- phenols with an electron-withdrawing substituent are generally more acidic since the substitutents delocalize the negative charge - phenols with an electron-donating substituent are generally less acidic since the substitutents destabilize the phenoxide ion
Resonance Stabilization of the Phenoxide Ion
6
Preparation of Alcohols Review 1) hydration of alkenes by way of hydroboration/oxidation and oxymercuration/reduction H3C
H3C
H
BH3 THF
-OH
BH2
H
OH
H
CH3
1-methylcyclohexene
H
H2O2
trans-2-methylcyclohexanol H3C Hg(OAc)2
NaBH4
OH
H2 O
H3C OH
H HgOAc
1-methylcyclohexanol
2) hydroxylation of an alkene with OsO4 followed by reduction with NaHSO3 H3C OsO4
O
O Os
pyridine
H
O
O
H
Hg(OAc)2 H2 O
OH
OH
1-methylcis-1,2-cyclohexanediol
CH3
1-methylcyclohexene
H3C NaHSO3
CH3 O H
1-methyl-1,2-epoxycyclohexane
HO H3O+
H
CH3 OH
1-methyltrans-1,2-cyclohexanediol
7
Reduction of Carbonyl Compounds O
OH
[H]
C
C
Reduction of Aldehydes and Ketones - aldehydes are reduced to primary alcohols and ketones are reduced to secondary alcohols OH
O [H]
C
R
R
H
aldehyde
C H
primary alcohol
OH
O R
H
[H]
C
R
R'
ketone
C R'
H
secondary alcohol
Reagents for Aldehyde and Ketone Reduction O CH3CH2CH2
C
OH
1. NaBH4, EtOH
H
H3CH2CH2C
2. H3O+
C
H
H
butanal
1-butanol (85%) O
OH
H
1. NaBH4, EtOH
C
C
2. H3O+
dicyclohexyl ketone
dicyclohexylmethanol (88%)
O
OH
H 1. LiAlH4, ether 2. H3
2-cyclohexanone
C
O+
- sodium borohydride NaBH4 is usually chosen because of its safety and ease of handling
2-cyclohexenol
8
Reduction of Carboxylic Acids and Esters
O R
C
O
or OH
R
C
OH
[H] R
OR'
C H
H
primary alcohol
- carboxylic acids and esters are reduced to give primary alcohols
Examples O CH 3(CH 2)7CH
CH(CH 2)7 COH
1. LiAlH4, ether 2. H3O+
9-octadecenoic acid
CH(CH2)7CH2OH
9-octadecen-1-ol (87%)
O CH3CH2CH
CH3(CH2)7CH
CH COCH3
1. LiAlH4, ether
CH3CH2CH
CHCH2OH
2. H3O+
methyl-2-pentenoate
2-penten-1-ol (91%)
- NaBH4 reduces esters slowly and does not reduce carboxylic acids; LiAlH4 reduces all carbonyl groups
Mechanism - can be regarded to involve attack of a hydride ion to the positively polarized, electrophilic carbon atom of the carbonyl group
O C
carbonyl compound
H
O C
OH
H
alkoxide intermediate
C
H
alcohol
- protonation by acid gives the alcohol
9
Reactions with Grignard Reagents R
X
R
MgX
Grignard reagent
R = 1o, 2o, or 3o alkyl, aryl, vinylic X = Cl, Br, or I
O
OH
1. RMgX, ether
C
C
2. H3O+
+ HOMgX R
Formaldehyde Reaction O
MgBr
+ H
cyclohexylmagnesium bromide
C
CH2OH
1. Mix 2. H3O+
H
formaldehyde
cyclohexylmethanol (65%)
Aldehyde Reaction CH3 H3C
C
O
MgBr
+
CH2 CH
1. ether solvent 2. H3
H
3-methylbutanal
CH3 H3C
O+
phenylmagnesium bromide
OH
C
CH2 C
H
H
3-methyl-1-phenyl-1butanol (73%)
Ketone Reaction O
OH
1. CH3CH2MgBr, ether 2. H3
CH2CH3
O+
cyclohexanone
1-ethylcyclohexanol (89%)
Ester Reaction O CH3CH2CH2CH2
C OCH2CH3
ethylpentanoate
1. CH3CH2MgBr, ether 2. H3
O+
OH CH3CH2CH2CH2
C CH3 CH3
2-methyl-2-hexanol (85%)
+ CH3CH2OH
10
Carboxylic Acid Reaction O
RMgBr
+ R'
C
O
RH + OH
R'
carboxylic acid
C
O
+MgBr
carboxylic acid salt
- carboxylic acids do not give addition products with Grignard reagents because the acidic carboxyl hydrogen reacts with the basic Grignard reagent to yield a hydrogen carbon (RH) and magnesium salt of the acid
Limitations of Grignard Reagents - Grignard reagent cannot be prepared from an organohalide if there are other reactive functional groups in the same molecule - this limits the structures of the products Br
FG
molecule
- Grignard cannot be made where FG = protonate Grignard
= -OH, -NH, -SH, -COOH
=
O
O
O
CH ,
CR ,
CNR2
C
N,
NO2 ,
adds to Grignard
SO2R
Mechanism
O C
carbonyl compound
R
O C
H3O+
R
alkoxide intermediate
OH C
R
alcohol
- Grignard reagent acts as a nucleophilic carbon anion, or carbanion; the addition of the Grignard is analogous to the addition of a hydride
11
Reactions of Alcohols H O
C-O reactions
O-H reactions
C
Dehydration of Alcohols (C-O bond) H
OH C
C
C
+
C
H2O
- a number of methods have been developed: 1) acid-catalyzed dehydration (mild) 2) acid-catalyzed dehydration (harsh) 3) phosphorus oxychloride
Acid-catalyzed dehydration H3C
CH3
OH H3O+, THF 50oC
1-methylcyclohexene (91%)
1-methylcyclohexanol
CH3 H3C
C
CH2CH3
OH 2-methyl-2butanol
H3O+, THF 25oC
CH3
CH3 CHCH3 +
CH3 2-methyl-2-butene (trisubstituted)
CH2CH3 CH3 2-methyl-1-butene (disubstituted)
- acid-catalyzed reaction follows Zaitsev’s rule, giving the more highly substituted alkene as major product - E1 mechanism that involves three steps
12
Reactivity OH
OH R
C
R
> R
C
OH H
>
C
R
R
R
H
H
reactivity - tertiary substrates always react fastest in E1 reactions because they lead to highly stabilize tertiary carbocation intermediates
Mechanism
Phosphorus Oxychloride
CH3 OH
CH3
POCl3 pyridine, OoC
H 1-methylcyclohexanol
1-methylcyclohexene (96%)
- E2 mechanism, -OPOCl2 is excellent leaving group - pyridine serves as both solvent and base
13
Mechanism
Conversion of Alcohols into Alkyl Halides (C-O Bond)
RCH2OH
RCH2OH
SOCl2
PBr3
RCH2Cl + SO2 + HCl
RCH2Br + HOPBr2
- tertiary alcohols are converted using HCl or HBr at OoC through an SN1 mechanism - secondary and primary alcohols are resistant to acid and are converted using either SOCl2 or PBr3 through an SN2 mechanism
Mechanism
14
Conversion of Alcohols into Tosylates (O-H Bond) CH3
R
O
H
alcohol
+
Cl O
CH3
pyridine S O
p-toluenesulfonyl chloride
R
O O
+
S O
tosylate
pyridine·HCl
- reaction produces alkyl tosylates which are synthetically useful since they behave like alkyl halides - in contrast to alkyl halides, the products undergo only one Walden inversion to form a product - the product is therefore of opposite stereochemistry relative to the reactants
15
Oxidation of Alcohols OH C
O
oxidize
H
C
reduce
Primary Alcohol OH R
C H
O
[O]
R
H
C
O
[O]
R
H
aldehyde
C
O
H
carboxylic acid
Secondary Alcohol OH R
C R'
O
[O]
R
H
C
R'
ketone
Tertiary Alcohol OH R
C R'
[O]
R''
NO REACTION
Reagents - large number of reagents can be used: KMnO4, CrO3, Na2CrO7 - depends on factors such as cost, convenience, reaction yield, and alcohol sensitivity
16
Preparation of an Aldehyde from a Primary Alcohol on Laboratory Scale - use of pyridinium chlorochromate (PCC) O
PCC CH2OH
C
CH2Cl2
citronellol
H
citronellal (82%) PCC =
N
H CrO3Cl-
- most other oxidizing agents oxidize primary alcohols to carboxylic acids O
CH3(CH2)8CH2OH
CrO3
CH3(CH2)8
H3O+, acetone
C
OH
decanoic acid (93%)
1-decanol
Secondary Alcohols to Give Ketones - large scale and inexpensive, use Na2Cr2O7: CH3 H3C
CH3
Na2Cr 2O7
C
OH
H3C
H2O, CH3CO2H, heat
CH3
C
O
CH3
4-tert-butylcyclohexanol
4-tert-butylcyclohexanone (91%)
- for sensitive alcohols, use PCC: CH3 O
CH3 OH
PCC
CH3
CH3
CH2Cl2, 25oC O
O
4-androstene-3,17-dione (82%)
testosterone
Mechanism - pathway closely related to E2 reaction
Base
O H
O O C
H
Cr
O
H
O Cr
O C
O O O
H
Cr O C
H
O
O
O
E2
H Base
chromate intermediate
C
carbonyl compound
- reaction produces a C-O bond (compare to C-C bond)
17
Protection of Alcohols - it is often necessary to circumvent synthetic incompatibilities using protecting groups 1) introduce the protecting group 2) carry out the desired reaction 3) remove the protecting group
Mg
HO CH2CH2CH2
x
Br
HO CH2CH2CH2
MgBr
Ether
Trimethylsilyl (TMS) ether - common protecting group for alcohols is trimethylsilyl (TMS) ether
CH3 ROH
alcohol
+
H3C
Si
Cl
(CH3CH2)3N
CH3 R
Si
CH3 +
(CH3CH2)3NH+ Cl-
CH3
CH3
chlorotrimethylsilane
O
a trimethylsilyl ether
Example OH
+ (CH3)3SiCl
cyclohexanol
(CH3CH2)3N
OSi(CH3)3
cyclohexyl trimethylsilyl ether (94%)
18
Removal of the Protecting Group - protecting group can be removed using acid or with fluoride ion
O
CH3
Si
OH
H3O+
+ (CH3)3SiOH
CH3
CH3
cyclohexanol
cyclohexyl TMS ether
Preparation of Phenols Dow Process Cl
OH 1. NaOH, H2O, 340oC, 2500 psi 2. H3O+
Alternative Synthesis H H3C
C
OOH CH3
O2
H3C
C
CH3
OH O
H3O+
+
heat
cumene
cumene hydroperoxide
phenol
H3C C CH 3
acetone
Mechanism
19
Acetal O
OR'
Acid
+ 2R’OH
C
C
catalyst
OR'
Hemiacetal OH C
OR'
Laboratory Preparation
OH
SO3H
SO3
1. NaOH, 300oC
H2SO4
2. H3O+
CH3
CH3
toluene
CH3
p-methylphenol (72%)
p-toluenesulfonic acid
- owing to the harsh reaction conditions, the reaction is limited to alkyl-substituted phenols
Uses of Phenols OH Cl
OCH2COOH Cl
Cl
Cl
Cl Cl
Cl
pentachlorophenol (wood preservative)
2,4-dichlorophenoxyacetic acid (herbicide) 3
OH Cl
Cl
OH
OH Cl
C(CH3)3
(H3C)3C
Cl Cl Cl
Cl
hexachlorophene (antiseptic)
CH3
butylated hydroxytoluene (food preservative)
20
Reactions of Phenols 1) Electrophilic Aromatic Substitution - -OH group is strongly activating, ortho- and para-directing - phenol is therefore highly reactive for electrophilic halogenation, nitration, sulfonation, Friedel-Crafts reactions Y HO
HO
Y
para-
ortho-
2) Oxidation of Phenols - oxidation yields 2,5-cyclohexadiene-1,4-dione or quinone - reactions can be accomplished with Na2Cr2O7 and (KSO3)2NO O
OH (KSO3)2NO H2O
O
phenol
benzoquinone (70%)
Reversible Oxidation - oxidation-reduction (redox) properties of quinones makes quinones a valuable class of compounds O
OH SnCl2, H2O Fremy’s salt
O
benzoquinone
OH
hydroquinone
21
Ubiquinones O H3CO
CH3 CH3 (CH2 CH CCH2)nH
H3CO O
- redox behavior is found in biology, where compounds known as ubiquinones act as biochemical oxidizing agents to mediate electron-transfer processes in the mitochondria
Energy Production in the Mitochondria O H3CO
OH CH3
H3CO
CH3
R
H3CO
R
+ NAD+
NADH + H+ + H3CO O
OH O
OH H3CO
CH3
H3CO
R
H3CO
CH3
H3CO
R
+ H2O
+ ½O2 O
OH
NADH + ½O2 + H+
NAD+ + H2O
Spectroscopy of Alcohols and Phenols Infrared Spectroscopy - alcohols characteristic O-H stretching absorption at 3300 - 3600 cm-1 - depends upon the extent of hydrogen bonding - unassociated: sharp absorption at 3600 cm-1 - hydrogen bonds: broad absorption at 3300 - 3400 cm-1 - strong C-O stretching band near 1050 cm-1 - phenols broad absorption at 3500 cm-1 plus aromatic bands at 1500 and 1600 cm-1
22
Infrared Spectrum of Cyclohexanol
Infrared Spectrum of Phenol
NMR Spectroscopy 69.5 δ
OH
- 13C NMR spectra:
35.5 δ 24.4 δ 25.9 δ
- 1H NMR spectra:
- hydrogens on oxygen-bearing carbons are deshielded (3.5. - 4.5 δ) - hydrogen atom of -OH undergoes exchange:
C
O
H
H’A
C
H
O
H'
O
D
H D2O
C
O
H
C
(can exchange hydrogen for deuterium)
23
1H
NMR Spectrum of 1-Propanol
Mass Spectrometry - alcohols fragment by two pathways: alpha cleavage and dehydration +.
+
OH R
C
OH CH2R
R
R
C
+ . CH2R
R
+.
+. OH
H C
C
H2O +
C
C
- both fragments are apparent in mass spectra
Mass Spectrum of 1-Butanol
24
